PKCλ/ι inhibition activates an ULK2-mediated interferon response to repress tumorigenesis.

The interferon (IFN) pathway is critical for cytotoxic T cell activation, which is central to tumor immunosurveillance and successful immunotherapy. We demonstrate here that PKCλ/ι inactivation results in the hyper-stimulation of the IFN cascade and the enhanced recruitment of CD8+ T cells that impaired the growth of intestinal tumors. PKCλ/ι directly phosphorylates and represses the activity of ULK2, promoting its degradation through an endosomal microautophagy-driven ubiquitin-dependent mechanism. Loss of PKCλ/ι results in increased levels of enzymatically active ULK2, which, by direct phosphorylation, activates TBK1 to foster the activation of the STING-mediated IFN response. PKCλ/ι inactivation also triggers autophagy, which prevents STING degradation by chaperone-mediated autophagy. Thus, PKCλ/ι is a hub regulating the IFN pathway and three autophagic mechanisms that serve to maintain its homeostatic control. Importantly, single-cell multiplex imaging and bioinformatics analysis demonstrated that low PKCλ/ι levels correlate with enhanced IFN signaling and good prognosis in colorectal cancer patients.

Utility of Assessing Early Tumor Shrinkage as an Efficacy Predictor in Patients with Non-Surgically Indicated or Recurrent Esophageal Cancer Treated with Nivolumab plus Ipilimumab.

INTRODUCTION: Nivolumab plus ipilimumab combination therapy has been administered as a first-line treatment in Japan since 2022 for patients with unresectable progressive or recurrent esophageal cancer. The efficacy and safety of this immune checkpoint inhibitor (ICI) doublet therapy are now being evaluated, and it is necessary to identify populations that benefit from this treatment at an early phase after initiation. For patients not showing early benefit, changing as soon as possible to other therapeutic strategies could improve their survival outcomes. Therefore, we attempted to identify decision-making factors such as early tumor shrinkage (ETS) based on treatment experience with ICI doublet therapy. METHODS: The study included 19 patients who received nivolumab plus ipilimumab for non-surgically indicated or recurrent esophageal cancer between July 2022 and November 2023. Tumors were assessed approximately every 2 months after treatment initiation. The effects of ETS, depth of response (DpR), and clinicopathologic features, including immune-related adverse events (irAEs), on progression-free and overall survival were evaluated using Kaplan-Meier plots and Cox proportional hazard models. RESULTS: The mean duration of ICI doublet administration was 5.89 months (range, 1-16 months). At first evaluation, patients who exhibited no tumor progression >20% indicated possible response to ICI doublet therapy, and patients whose tumors shrank even minimally exhibited favorable progression-free survival. Higher DpR at any cut-off line exhibited better progression-free survival than those with lower DpR. Fifteen patients experienced irAEs, with 13 of these patients experiencing irAEs within 3 months of treatment initiation. irAEs were associated with the efficacy of ICI doublet therapy, but efficacy could not be predicted based on early irAE experience. CONCLUSION: ETS-high, DpR-high, and irAEs might be associated with favorable responses to nivolumab plus ipilimumab. As a predictor of efficacy at an early phase, ETS >0% could be a deciding factor for continuing ICI doublet therapy.

Robot-assisted minimally invasive esophagectomy for esophageal cancer in the left lateral decubitus position.

BACKGROUND: The use of robot-assisted minimally invasive esophagectomy (RAMIE) in the prone position for esophageal cancer has been currently increasing worldwide. In future, as surgical-assisted robots become more widespread, it is estimated that only two methods of transthoracic approach will remain: RAMIE and open thoracotomy for thoracic esophageal cancer. RAMIE in the left lateral decubitus position (RAMIE-LLDP) has the same field of view as open thoracotomy, is safe in emergency situations, and provides education on open thoracotomy. METHODS: Between September 2020 and April 2024, RAMIE-LLDP was performed in 64 consecutive patients with esophageal cancer. RAMIE-LLDP was performed with the operating table rotated and tilted 45° to the ventral side under artificial pneumothorax. The hand-control setting of the surgical-assist robot system was reversed left to right when the Patient Cart was rolled from the same direction as the RAMIE in the prone position. RESULTS: The mean total surgery and console times during the thoracic procedure were 254-min overall and 225 min in the last 24 cases and 195-min overall and 178- min in the last 24 cases, respectively. The mean amount of blood loss was 203.4 g overall and 28.3 g in the last 24 cases. Postoperative recurrent laryngeal nerve palsy with Clavien-Dindo classification (CD) was ≥ 2 in six patients (9.4%). Postoperative pneumonia with CD ≥ 2 was observed in 11 patients (17.2%). Conversion to open thoracotomy was observed in three patients (4.7%). In all three patients, an immediate conversion to thoracotomy without patients' position change was actually possible and no serious complications were noted. No mortality occurred within 30 days postoperatively. CONCLUSION: RAMIE-LLDP which facilitates emergency thoracotomy has perioperative results comparable to those of conventional thoracoscopic esophagectomy and is educational for open surgery. RAMIE-LLDP is the safest and most optimal surgery for esophageal cancer.

Optimal extent of lymph node dissection for high-risk gastric cancer stratified by a national clinical database risk calculator.

BACKGROUND: For patients with gastric cancer, a well-balanced treatment that considers both oncological aspects and surgical risk is demanded. This study aimed to explore the optimal extent of lymph node dissection (LND) for patients with gastric cancer according to surgical risk, stratified by the risk calculator system produced by the Japan National Clinical Database (NCD). PATIENTS AND METHODS: We retrospectively evaluated 187 patients who underwent radical gastrectomy for gastric cancer. Using the median predicted anastomotic leak rate obtained by the NCD risk calculator as the cutoff value, we classified 97 and 90 patients as having high and low risks, respectively. RESULTS: In low-risk patients, although limited LND reduced the postoperative intraabdominal infectious complications (IAIC), multivariate analysis revealed standard LND as an independent prognostic factor that improved Relapse-free survival (RFS). In high-risk patients, the rates of postoperative IAIC and RFS were similar between standard and limited LND. Pancreatic fistula was not observed in the limited dissection group. CONCLUSION: Limited LND might be the optimal treatment strategy for patients with gastric cancer with high surgical risk.

Effects of an artificial pancreas on postoperative inflammation in patients with esophageal cancer.

PURPOSES: Subtotal esophagectomy for esophageal cancer (EC) is associated with high morbidity rates. Tight glycemic control using an artificial pancreas (AP) is one of the promising strategies to reduce postoperative inflammation and morbidities. However, the effects of tight glycemic control using AP in patients with EC are yet to be fully elucidated. METHOD: This study reviewed 96 patients with EC who underwent subtotal esophagectomy. The postoperative inflammation parameters and morbidity rates were compared between patients who used the AP (n = 27) or not (control group, n = 69). AP is a closed-loop system that comprises a continuous glucose monitor and an insulin pump. RESULTS: The numbers of white blood cells (WBC) and Neutrophils (Neut) were noted to be lower in the AP group than in the control group, but with no significant difference. The ratio in which the number of WBC, Neut, and CRP on each postoperative day (POD) was divided by those tested preoperatively was used to standardize the results. The ratio of WBC and Neut on 1POD was significantly lower in the AP group than in the control group. The rate of surgical site infection was lower in the AP group than in the control group. CONCLUSION: AP significantly decreased WBC and Neut on 1POD; this suggests the beneficial effects of AP in alleviating postoperative inflammation.

The heterogeneity of cancer-associated fibroblast subpopulations: Their origins, biomarkers, and roles in the tumor microenvironment.

The prognosis for patients with cancers known for a highly activated stromal reaction, including diffuse-type (scirrhous) gastric cancer, consensus molecular subtype 4 (CMS4) colorectal cancer, and pancreatic ductal adenocarcinoma, is extremely poor. To explore the resistance of conventional therapy for those refractory cancers, detailed classification and investigation of the different subsets of cancer-associated fibroblasts (CAFs) involved are needed. Recent studies with a single-cell transcriptomics strategy (single-cell RNA-seq) have demonstrated that CAF subpopulations contain different origins and marker proteins with the capacity to either promote or suppress cancer progression. Through multiple signaling pathways, CAFs can promote tumor growth, metastasis, and angiogenesis with extracellular matrix (ECM) remodeling; they can also interact with tumor-infiltrating immune cells and modulate the antitumor immunological state in the tumor microenvironment (TME). Here, we review the recent literature on the various subpopulations of CAFs to improve our understanding of the cell-cell interactions in the TME and highlight future avenues for CAF-targeted therapy.

Prognostic significance of the Naples prognostic score in colorectal cancer patients undergoing curative resection: a propensity score matching analysis.

BACKGROUND: Systemic inflammation is recognized as a hallmark of cancer that contributes to tumor development and progression in various malignancies. The Naples prognostic score (NPS) was established as a prognostic indicator for colorectal cancer (CRC). This study aims to examine the predictive value of the NPS for survival in CRC patients undergoing curative resection by a propensity score matching (PSM) analysis. METHODS: A total of 533 CRC patients were enrolled in this study. Overall survival (OS) and disease-free survival (DFS) were compared between high-NPS and low-NPS groups. A time-dependent receiver operator characteristic (ROC) curve analysis was conducted to calculate the area under curve (AUC) of the NPS for OS. A multivariable Cox-proportional hazards regression analysis and PSM analysis were used to identify independent prognostic factors for OS and DFS. We compared the predictive value of the NPS to that of the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), Onodera prognostic nutritional index (PNI), and controlling nutritional status score (CONUT) for OS. RESULTS: High-NPS was significantly associated with worse OS and DFS. After PSM, 123 patients were included in each group. A multivariate analysis revealed that Age ≥ 68, ASA-PS ≥ 3, high NPS and undifferentiated tumor type were independently associated with OS, while high NPS, advanced T and N stage were independently associated with DFS after PSM. The NPS had the greatest AUC for OS in comparison to the NLR, LMR, PNI and CONUT. CONCLUSIONS: We successfully validated the prognostic utility of the NPS for CRC patients after curative resection.

Predictive value of the Naples prognostic score on postoperative outcomes in patients with rectal cancer.

PURPOSE: The Naples prognostic score (NPS) is a prognostic index based on the nutritional and inflammatory status. However, its utility in predicting postoperative complications (POCs) has not been examined in rectal cancer (RC). We evaluated the predictive value of the preoperative NPS for POCs in RC. METHODS: We retrospectively analyzed 235 patients who underwent surgery for RC. The NPS was calculated based on serum albumin, serum total cholesterol, the neutrophil-to-lymphocyte ratio (NLR) and the lymphocyte-to-monocyte ratio (LMR). Severe POCs were defined as Clavien-Dindo classification grade ≥ III. The optimal cut-off value of the NPS was determined by a receiver operator characteristic (ROC) curve analysis. The NPS, NLR, LMR, platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP)-to-albumin ratio (CAR), Glasgow prognostic score (GPS), Onodera prognostic nutritional index (PNI) and controlling nutritional status score (CONUT) were investigated as inflammation-based and/or nutritional markers. Predictors of severe POCs were analyzed by logistic regression modeling. RESULTS: Severe POCs were observed in 64 patients (27.2%). Male sex, operation time (> 257 min), blood loss (≥ 30 mL), albumin (< 4.0 g/dL), CRP (≥ 1.0 mg/dL), total cholesterol (≤ 180 mg/dL), NPS (≥ 2), LMR (≥ 3.48), PLR (≥ 103.6), CAR (> 0.025), GPS (≥ 1), PNI (< 48.1) and CONUT (≥ 2) were significantly associated with severe POCs. The multivariate analysis revealed that male sex, operation time (> 257 min), and a high NPS (≥ 2) were independent predictors of severe POCs. The ROC curve analysis revealed that the NPS had the greatest predictive value among the inflammation-based and/or nutritional markers. CONCLUSION: The NPS is a valuable predictor of severe POCs in RC.

Impact of a circular powered stapler on preventing anastomotic leakage in patients with left-sided colorectal cancer: a retrospective study.

BACKGROUND: The powered circular stapler, which was developed with the aim of providing reliable and reproducible anastomosis, provides complete anastomosis, resulting in a reduced risk of anastomotic leakage. The aim of this study was to compare the incidence of anastomotic leakage between a conventional manual circular stapler (MCS) and the ECHELON CIRCULAR™ Powered Stapler (ECPS) in patients with left-sided colorectal cancer who underwent anastomosis with the double stapling technique. METHODS: A total of 187 patients with left-sided colorectal cancer who underwent anastomosis with the double stapling technique with a conventional MCS or the ECPS during surgery at Osaka City University Hospital between January 2016 and July 2022 were enrolled in this study. RESULTS: The incidence of anastomotic leakage in the ECPS group was significantly lower than that in the MCS group (4.4% versus 14.3%, p = 0.048). Furthermore, even after propensity score matching, an association was found between the use of the ECPS and a reduced incidence of anastomotic leakage. CONCLUSION: The ECPS has the potential to help reduce the rate of anastomotic leakage in left-sided colorectal surgery.

Efficacy of the polyglycolic acid sheet for preventing anastomotic leakage in double-stapling technique anastomosis for left-sided colon or rectal cancer surgery: a propensity score-matched study.

BACKGROUND: To prevent anastomotic leakage in patients with left-sided colorectal cancer who underwent double-stapling technique (DST) anastomosis, we investigated a new method: DST anastomosis with a polyglycolic acid (PGA) sheet. This procedure has been shown to have the potential to decrease the rate of anastomotic leakage. However, due to the small number of cases enrolled in our previous study, it was not possible to compare the outcomes of the new and conventional procedures. The aim of this study was to evaluate the effect of the PGA sheet on preventing anastomotic leakage in patients with left-sided colorectal cancer who underwent DST anastomosis by retrospectively comparing the anastomotic leakage rate between the PGA sheet and conventional groups. METHODS: A total of 356 patients with left-sided colorectal cancer who underwent DST anastomosis during surgery at Osaka City University Hospital between January 2016 and April 2022 were enrolled in this study. Propensity score matching was performed to reduce the confounding effects secondary to imbalances in the use of PGA sheets. RESULTS: The PGA sheet was used in 43 cases (PGA sheet group) and it was not used in 313 cases (conventional group). After propensity score matching, the incidence of anastomotic leakage in the PGA sheet group was significantly lower than that in the conventional group. CONCLUSION: DST anastomosis with PGA sheet, which is easy to perform, contributes to the reduction of anastomotic leakage rate by increasing the strength of the anastomotic site.

[The Role of Cancer-Associated Fibroblasts in Modulating Tumor Immunity in Colorectal Cancer].

Cancer-associated fibroblasts(CAFs)remodel the extracellular matrix(ECM)and shape the tumor microenvironment (TME), resulting in immune escape and the promotion of tumor metastasis. Using an orthotopic tumor model of colorectal cancers(CRCs)in mice, we demonstrated that the single-cell RNA sequencing of orthotopic rectal tumors identified a subpopulation of CAFs that modulate the immune response. In this review, we report that understanding the role of CAFs in the TME concerning tumor immunity may lead to future avenues for CAF-targeted therapy.

[A Case of Robot-Assisted Abdominoperineal Resection Alongside En Bloc Prostatectomy and Vesico-Urethral Anastomosis for Local Recurrence].

A 66-year-old man presenting with cStage Ⅲc rectal cancer underwent laparoscopic low anterior resection(D3 lymph node dissection and R0 resection)following neoadjuvant chemoradiotherapy(capecitabine, 45 Gy/25 Fr)and received adjuvant chemotherapy(CAPOX). A year after surgery, abdominal contrast-enhanced computed tomography revealed recurrence near the rectal anastomosis with prostate invasion. The patient underwent robot-assisted abdominoperineal resection alongside en bloc prostatectomy and vesico-urethral anastomosis after 12 courses of neoadjuvant chemotherapy(FOLFIRI and panitumumab). He exhibited a good postoperative course and was discharged on the 12th postoperative day. After 7 months of surgery, no recurrence was observe; and urinary incontinence seen immediately after surgery gradually improved.

[A Case of Late Recurrence of Anal Canal Carcinoma after Surgery, Discovered following the Diagnosis of a Subcutaneous Tumor in the Perineal Region].

We present an 82-year-old male patient who underwent laparoscopic abdominal perineal rectal amputation and D3 lymph node dissection, including left inguinal lymph node dissection for anal canal carcinoma. Left inguinal lymph node metastasis was positive, and pT1bN2aM0, pStage Ⅲa was the final pathological diagnosis. He underwent 8 courses of capecitabine plus oxaliplatin therapy as adjuvant chemotherapy. He was examined without recurrence for 5 years postoperatively. However, he awared a perineal subcutaneous tumor and was transferred to our hospital for further examination and treatment 6 years postoperatively. Recurrence after anal canal carcinoma surgery was diagnosed based on a needle biopsy, and perineal subcutaneous tumor resection was performed. This is a rare case of late postoperative recurrence of anal canal carcinoma, which was detected due to a perineal subcutaneous tumor 6 years after surgery for anal canal carcinoma.

[A Case of Sigmoid Colon Cancer with Simultaneous Solitary Adrenal Metastasis Refractory to Preoperative Diagnosis].

A 72-year-old man was referred to our urology department due to a giant adrenal tumor detected by computed tomography( CT). Endocrine screening showed that cortisol, renin, aldosterone, adrenaline, and noradrenaline levels were all normal, and there was no evidence of adrenal hyperfunction. The adrenal tumor was so large that we suspected malignancy. Contrast-enhanced CT of the abdomen was performed for qualitative diagnostic purposes, and showed wall thickening of the sigmoid colon extending for approximately 6 cm. Lower gastrointestinal endoscopy was performed and revealed a full circumferential type 2 tumor in the sigmoid colon. Biopsy results showed intermediate differentiated ductal adenocarcinoma. Tumor markers were as follows: CEA 23.1 ng/mL, CA19-9 962 U/mL. The adrenal tumor was suspected of being malignant due to its size, but imaging examinations did not lead to a diagnosis of primary or metastatic disease. There were no tumors other than those in the sigmoid colon and adrenal glands. Since complete resection was deemed possible, sigmoid colon resection and combined left adrenalectomy were performed for both a diagnosis and treatment. A histopathological examination revealed that the histology of the adrenal tumor resembled that of colorectal cancer, leading to a diagnosis of left adrenal metastasis from sigmoid colon cancer.

[A Case of Advanced Recurrent Rectal Cancer Successfully Treated by Rechallenge Therapy with an Anti-Epidermal Growth Factor Receptor(EGFR)Drug].

The patient was a 75-year-old man who had undergone potentially curative surgery for Stage Ⅲb rectal cancer followed by resection of liver metastases. Two years after the resection of liver metastases, lung and remnant liver metastases were found. He received chemotherapy for unresectable metastatic tumors. Based on the findings of molecular and pathological examinations(RAS: wild type; BRAF: wild type; MSI: negative; HER2: negative), the following chemotherapy regimens were administered: first-line, FOLFIRI plus panitumumab(PANI); second-line, mFOLFOX6; third-line, trifluridine/tipiracil; fourth- line, regorafenib. After fourth-line treatment, he was judged to have disease progression due to the increase in his lung and liver metastases and the elevation of tumor markers. All standard regimens were refractory, but the Eastern Cooperative Oncology Group performance status was zero and a liquid biopsy for RAS still showed wild type. Therefore, rechallenge therapy with anti-epidermal growth factor receptor(EGFR)drugs, cetuximab(CET)and irinotecan(IRI), was administered 13 months after the final course of FOLFIRI plus PANI treatment. After 4 courses of CET plus IRI, the size of the 2 metastatic tumors markedly decreased and his tumor marker levels normalized.

Significance of tumor heterogeneity of p-Smad2 and c-Met in HER2-positive gastric carcinoma with lymph node metastasis.

BACKGROUND: Tumor heterogeneity has frequently been observed in gastric cancer (GC), but the correlation between patients' clinico-pathologic features and the tumoral heterogeneity of GC-associated molecules is unclear. We investigated the correlation between lymph node metastasis and the intra-tumoral heterogeneity of driver molecules in GC. MATERIALS AND METHODS: We retrospectively analyzed the cases of 504 patients who underwent a gastrectomy at the Department of Gastroenterological Surgery, Osaka Metropolitan University and 389 cases drawn from The Cancer Genome Atlas (TCGA) data. We performed a clustering analysis based on eight cancer-associated molecules including HER2, c-Met, and p-Smad2 using the protein expression revealed by our immunohistochemical study of the patients' and TCGA cases. We determined the correlations between HER2 expression and the other molecules based on the degree of lymph node metastasis. RESULTS: Immunohistochemical staining data showed that a 43 of the 504 patients with GC (8.5%) were HER2-positive. In the HER2-positive cases, the expressions of c-Met and p-Smad2 were increased in accord with the lymph-node metastatic level. The overall survival of the HER2-positive GC patients with both p-Smad2 and c-Met expression was significantly (p = 0.030) poorer than that of the patients with p-Smad2-negative and/or c-Met-negative expression. The results of the TCGA data analysis revealed that 58 of the 389 GC cases (14.9%) were ERBB2-positive. MET expression was more frequent in the N1 metastasis group than the N0 group. In the high lymph-node metastasis (N2 and N3) group, SMAD2 expression was more frequent, as was ERBB2 and MET expression. CONCLUSION: p-Smad2 and c-Met signaling might play important roles in lymph node metastasis in HER2-positive GC.

Lipocalin-2 negatively regulates epithelial-mesenchymal transition through matrix metalloprotease-2 downregulation in gastric cancer.

BACKGROUND: Although the role of Lipocalin-2 (LCN2) in cancer development has been focused on recent studies, the molecular mechanisms and clinical relevance of LCN2 in gastric cancer (GC) still remain unclear. METHODS: Transcriptome analysis of GC samples from public human data was performed according to Lauren's classification and molecular classification. In vitro, Western blotting, RT-PCR, wound healing assay and invasion assay were performed to reveal the function and mechanisms of LCN2 in cell proliferation, migration and invasion using LCN2 knockdown cells. Gene set enrichment analysis (GSEA) of GC samples from public human data was analyzed according to LCN2 expression. The clinical significance of LCN2 expression was investigated in GC patients from public data and our hospital. RESULTS: LCN2 was downregulated in diffuse-type GC, as well as in Epithelial-Mesenchymal Transition (EMT) type GC. LCN2 downregulation significantly promoted proliferation, invasion and migration of GC cells. The molecular mechanisms of LCN2 downregulation contribute to Matrix Metalloproteinases-2 (MMP2) stimulation which enhances EMT signaling in GC cells. GSEA revealed that LCN2 downregulation in human samples was involved in EMT signaling. Low LCN2 protein and mRNA levels were significantly associated with poor prognosis in patients with GC. LCN2 mRNA level was an independent prognostic factor for overall survival in GC patients. CONCLUSIONS: LCN2 has a critical role in EMT signaling via MMP2 activity during GC progression. Thus, LCN2 might be a promising therapeutic target to revert EMT signaling in GC patients with poor outcomes.

Asporin Expression on Stromal Cells and/or Cancer Cells Might Be A Useful Prognostic Marker in Patients with Diffuse-Type Gastric Cancer.

BACKGROUND: Asporin (ASPN), a member of the proteoglycan family, has been shown to have a close correlation with cancer progression. It is not known whether ASPN is an oncogenic driver or a tumor suppressor in human gastric cancer. We sought herein to determine the relationship between ASPN expression and clinicopathological features of gastric cancer. PATIENTS AND METHODS: A total of 296 gastric cancer patients (diffuse type, n = 144; intestinal type, n = 152) were enrolled. The ASPN expression level in each case was analyzed by immunohistochemistry. RESULTS: ASPN was mainly found on stromal cells, especially on fibroblasts in tumor stroma, i.e., cancer-associated fibroblasts. The ASPN expression on either cancer cells or stromal cells was significantly high in macroscopic scirrhous-type tumors (p < 0.001) and histologically abundant stroma-type tumors (p < 0.001). Interestingly, a Kaplan-Meier survival curve of the 144 cases of diffuse-type gastric cancer revealed a significantly poorer prognosis in patients with ASPN-positive expression (p = 0.043; log rank) compared to those with ASPN-negative expression, but the prognoses were not significantly different in these subgroups of the 152 cases of intestinal-type gastric cancer. A multivariate analysis with respect to overall survival showed that ASPN expression on stromal cells and/or cancer cells was significantly correlated with overall survival in patients with diffuse-type gastric cancer (p = 0.041). CONCLUSION: In gastric cancer, ASPN was expressed mainly on stromal cells and partially on cancer cells. ASPN expression on stromal cells and/or cancer cells might be a useful prognostic marker in patients with diffuse-type gastric cancer.

Significance of the Lysyl Oxidase Members Lysyl Oxidase Like 1, 3, and 4 in Gastric Cancer.

BACKGROUND/AIMS: Lysyl oxidase (LOX) family members play a key role in modifying the primary tumor microenvironment by crosslinking collagens and elastin in the extracellular matrix. The aim of this study was to analyze the LOX-like (LOXL)1, LOXL3, and LOXL4 expressions in gastric cancer tissue by immunohistochemical staining. METHODS: The correlations between the clinicopathological features of 597 primary gastric carcinomas and LOX family members - LOXL1, LOXL3, and LOXL4 - were investigated by immunohistochemical studies. The effect of the transforming growth -factor ß1 (TGFß1) on the expressions of LOXL1, LOXL3, and LOXL4 in gastric cancer was examined using diffuse-type gastric cancer cell lines in vitro. RESULTS: The expressions of LOXL1, LOXL3, and LOXL4 were correlated with T invasion, lymph node metastasis, and lymphatic and venous invasion. LOXL1 expression was associated with histological intestinal-type and expanding growth patterns. The overall survival of patients with LOXL1-, LOXL3-, or LOXL4-positive cancer was poorer than those with negative cancer. LOXL3 and LOXL4 mRNA expressions were significantly high in diffuse-type gastric cancer cells with high invasion ability. TGFß decreased the LOXL1 expression and increased LOXL3 and LOXL4 expression. CONCLUSION: LOXL1, LOXL3, and LOXL4 expressions are associated with distant metastasis of gastric cancer.